Project Summary Abstract The hippocampus (HPC) is required for spatial representations and episodic memory formation, while the nucleus accumbens (NAc) is involved in encoding reward and the value of choices available to an animal. These brain regions comprise a crucial neural circuit for associating rewards with the events that precede them and the context in which the reward was received. This reward association process is critical for normal, memory-guided decision-making, but can also go awry in mental illnesses such as schizophrenia and drug addiction. The identification of a neural substrate for this process would therefore be key to our understanding of healthy learning and our ability to effectively treat mental illnesses involving the hippocampus and nucleus accumbens. This proposal focuses on hippocampal sharp-wave ripples (SWRs), coordinated reactivations of neuronal sequences which represent past experience, as a candidate mechanism for attributing rewards to the experiences leading up to them. SWRs in dorsal HPC (dHPC) are required for learning spatial tasks and are enhanced by receipt of reward. SWRs may therefore bind reward signals to spatial sequences during learning, as reflected in the reactivation of reward-encoding NAc cells during dHPC SWRs following behavior. However, only ventral HPC (vHPC) projects directly to the NAc, but nothing is known about vHPC SWRs during behavior or how vHPC engages NAc neurons. Our lack of knowledge about vHPC activity is a critical gap in our understanding of spatial reward learning. There is evidence suggesting that spatial representations in dHPC guide early task learning, while representations of task context in vHPC form later in learning and may help adapt learned reward associations to new contexts. SWRs may therefore perform complementary roles in each region, with dHPC SWRs linking reward to spatial trajectories, and vHPC SWRs flexibly linking reward to task contexts. We hypothesize that dHPC and vHPC are differentially engaged across learning, with SWR activity in each region supporting a shift from spatially guided task acquisition to contextually guided adaptive behavior, and that changes in NAc activity parallel this shift. We will test this hypothesis by recording neural activity simultaneously in dHPC, vHPC, and NAc of rats learning a spatial working memory task with changing reward contingencies (Aims 1 and 2), and by reversibly inactivating dHPC or vHPC during behavior (Aim 3). Aim 1: To test the hypothesis that dHPC and vHPC SWRs are differentially engaged across learning. Aim 2: To test the hypothesis that task-specific NAc firing patterns evolve in conjunction with a shift from dHPC to vHPC engagement across learning. Aim 3: To test the hypothesis that vHPC activity is necessary for adaptive reward learning and for driving task representations in NAc. Accomplishing these Specific Aims will elucidate the role of awake SWRs and NAc firing patterns as neural substrates for reward associations which underlie flexible, memory-guided behavior.